Submissions for variant NM_002524.5(NRAS):c.34G>A (p.Gly12Ser)

dbSNP: rs121913250

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212761	SCV000208917	pathogenic	not provided	2022-02-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 25691160, 16518851, 19047918, 19966803, 23334668, 28098151, 28594414, 26918529, 29146900)
Invitae	RCV001066799	SCV001231819	pathogenic	RASopathy	2023-06-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19966803, 21263000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NRAS protein function. ClinVar contains an entry for this variant (Variation ID: 177778). This missense change has been observed in individual(s) with clinical features of a RASopathy (PMID: 28098151, 28594414). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the NRAS protein (p.Gly12Ser).
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813397	SCV002060956	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-11-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001066799	SCV004029432	pathogenic	RASopathy	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: NRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). c.34G>A has been reported in the literature in neonates affected with cystic hygroma (example: Mason-Suares_NRAS_EJHG_2017) and an individual affected with Noonan Syndrome reported as a de novo occurrence (example: Altmuller_2017). At-least one study have reported this variant affects the normal activity of the protein (example: Motoda_2007). Other variants affecting the same residue have been classified as pathogenic in ClinVar (examples: CV ID 219097, 40469, 39648, 40470). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000158978	SCV000204071	pathogenic	Juvenile myelomonocytic leukemia; Noonan syndrome	2013-12-02	no assertion criteria provided	clinical testing	The Gly12Ser variant has been identified by our laboratory in one individual wit h juvenile myelomonocytic leukemia (JMML) and dysmorphic features. In addition, this variant has been reported in 3 other individuals with JMML (Yoshida 2009), and was not identified in large population studies. Functional studies have show n the Gly12Ser variant causes constitutive NRAS signaling in the absence of grow th factor (Cirstea 2010). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly12Ser var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other variants at the Gly12 residue in RAS genes (NRAS , KRAS, HRAS) have been associated with multiple cancers, highlighting the impor tance of this position in cell signaling (Schubbert 2007). While this variant ha s not been identified in individuals with classic features of Noonan syndrome, i t is likely due to the severe impact of the variant. In summary, this variant me ets our criteria for pathogenicity for JMML and Noonan-spectrum disorders (http: //pcpgm.partners.org/LMM).
Database of Curated Mutations (DoCM)	RCV000430288	SCV000503746	likely pathogenic	Myelodysplastic syndrome	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439216	SCV000503747	pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421993	SCV000503748	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433097	SCV000503749	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442594	SCV000503750	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421327	SCV000503751	pathogenic	Non-small cell lung carcinoma	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431995	SCV000503752	pathogenic	Melanoma	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445150	SCV000503753	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427184	SCV000503754	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only